This resubmission is one of a group of Interactive Research Project Grant applications, which have the broad objective of clarifying the role of genes in alcohol dependence and related disorders. Alcohol dependence is a common condition with a substantial genetic component. This application focuses on pre-clinical alcoholic liver disease in a community-based sample and will complement published studies on patients with more advanced disease. The objective is to identify risk factors able to predict which hazardous drinkers are at risk of eventual progression to liver disease. Successful identification of risk factors for alcoholic liver disease may lead to improvements in early identification of people at risk from their drinking, and early intervention to prevent progression to clinical disease. Known risk factors include lifetime quantity of alcohol consumed, and gender (women are more susceptible to alcoholic liver disease than men). The postulated risk factors to be studied are based on a small number of published studies on patients, and on our preliminary work with community samples. They include obesity and related metabolic disorders; iron overload; and allelic variation in a range of candidate genes concerned with alcohol metabolism, inflammatory response within the liver, fatty liver and fibrosis. The specific aims are to test whether the postulated risk factors affect the probability of liver dysfunction in hazardous drinkers, using biochemical liver function tests to detect pre-clinical liver damage. The enzyme liver function tests are abnormal in a substantial proportion (approximately 30-40%) of hazardous drinkers and offer an opportunity for noninvasive testing in large numbers of subjects. Subjects will be drawn from twins and their families who have participated in previous studies of alcohol use and dependence. They will have met DSM-IV criteria for alcohol dependence and/or have reported hazardous levels of alcohol intake in the previous studies. They will provide information on recent alcohol intake, and blood samples will be taken for biochemical testing and as a source of DNA for genotyping. Data will be analyzed using standard methods for twin studies and tests will be included for the effects of postulated phenotypic risk factors, for heritability of liver abnormality conditional on hazardous drinking, and for allelic association at candidate genes.